There has been extensive research in the area of biodegradable materials for controlled release of drugs. Biodegradable matrices for drug delivery are useful because they obviate the need to remove non-degradable drug depleted devices. The ideal polymeric formulation for delivering drug in a controlled matter would combine the characteristics of a biodegradable polymer carrier that is hydrophobic, be liquid enough to be injected at body temperature but increase its viscosity when injected into tissue to thereby better encapsulate the incorporated drug, be stable under common storage conditions, have a predictable controlled degradation profile, versatile degradation and drug release profiles for both hydrophilic or hydrophobic agents, be safely eliminated from the injection site and the body shortly after the drug has been depleted from the carrier, be made from natural components that degrade and eliminate from the body without causing acute or chronic toxicity, and easy to make at low cost.
A polymer for use in the ideal drug delivery formulation must be hydrophobic so that it retains its integrity and the incorporated drug for a suitable period of time when placed in biological systems, such as the body, and stable at common storage conditions, preferably room temperature for an extended period before use.
The purity of the starting materials used for the preparation of implantable biodegradable polymers is essential because impurities may provoke irritation and local toxicity to the implant site or even systemic toxicity in severe cases. In addition, impurities may affect the structure and physical properties on the polymer such as molecular weight, branching, and formation unwanted chemical bonds.
Many biodegradable polymers have been evaluated for their suitability for use as a matrix for drugs including polyesters, polycarbonates, natural and synthetic polyamides, polyphosphate esters, polyphosphazenes and polyanhydrides. While these polymers were found useful applications as drug carriers, still there is a need for a reliable polymer for short term drug release (i.e. one to twenty weeks) that degrade and eliminated from an implant site within thirty weeks.
Polyanhydrides are useful bioabsorbable materials for controlled drug delivery. They hydrolyze to dicarboxylic acid monomers when placed in aqueous medium. Since their introduction to the field of controlled drug delivery, about 15 years ago, extensive research has been conducted to study their chemistry as well as their toxicity and medical applications. Several review articles have been published on polyanhydrides for controlled drug delivery applications (see Domb, et al., “Polyanhydrides” in Handbook of Biodegradable Polymers (Domb, et al., eds.) Hardwood Academic Publishers, p. 135-159 (1997)).
The stability of polyanhydrides in solid state and dry chloroform solution has been studied. Polyanhydrides, such as PSA, decreased in molecular weight over time. The decrease in molecular weight shows first-order kinetics, with activation energies of 7.5 Kcal/mole-° K. The decrease in molecular weight was explained by an internal anhydride interchange mechanism, as revealed from elemental and spectral analysis. A similar decrease in molecular weight as function of time was also observed among the aliphatic-aromatic co-polyanhydrides and imide containing co-polyanhydrides. (Domb, et al., Macromolecules 22: 3200 (1989)).
The low melting point and the solubility of aliphatic polyanhydrides in common organic solvents such as methylene chloride, allows for the easy dispersion of drug into the polymer matrix. Drugs can also be incorporated via compression or melt molding processes. For example, drugs can be incorporated into a slab either by melt mixing the drug into the melted polymer or by solvent casting. Polymer slabs loaded with a drug can also be prepared by compression molding a powder containing the drug. Similarly, one can injection mold the drug-polymer formulation into beads or rods. Polymer films can be prepared by solvent evaporation by casting the polymer solution containing the drug onto a Teflon coated dish. Microsphere-based delivery systems can be formulated by common techniques, including solvent removal, hot-melt encapsulation and spray drying. However, it is essential that all processes be performed under anhydrous conditions to avoid hydrolysis of the polymer or absorption of water in the polymer mass which degrade the polymer with time during storage.
The degradation of polyanhydrides, in general, varies with a number of factors. These factors include the chemical nature and the hydrophobicity of the monomers used to produce the polymer, the level of drug loading in the polymeric matrix, the pH of the surrounding medium (the higher the pH, the more rapidly the polymers degrade), the shape and geometry of the implant (the degradation is a function of the surface area) and the accessibility of the implant to water (porous materials will degrade more rapidly than non-porous). The porosity in an implant is dependent on the method of fabrication. For example, a compression-molded device will degrade at a much more rapid rate than an injection molded device due to the presence of a higher porosity in the polymer as compared to the latter.
The degradation rates for a number of polyanhydrides are available in the literature. Most studies focused on the degradation of the clinically tested polyanhydrides, poly(CPP-SA) and poly(FAD-SA). In general, during the initial 10 to 24 hours of water incubation in aqueous medium, the molecular weight dropped rapidly with no loss in wafer mass loss. This period was followed by a fast decrease in wafer mass accompanied by a very small change in polymer molecular weight. The period of extensive mass loss starts when the polymer molecular weight reaches a number average molecular weight (Mn) of about 2,000 regardless of the initial molecular weight of the polymer. During this period which lasts for about one week, sebacic acid, the relatively water soluble comonomer, is released from the wafer leaving the less soluble comonomer, CPP or FAD, which is slow to solubilize (DANG, et al., J. Control. Rel. 42: 83-92 (1996)). Increasing the content of sebacic acid in the copolymer increases the hydrophilicity of the copolymer, which results in a higher erosion rate and hence higher drug release rates. This could be explained by the fact that the anhydride linkages in the polymer are hydrolyzed subsequent to penetration of water into the polymer. The penetration of water or water uptake depends on the hydrophobicity of the polymer and therefore, the hydrophobic polymers which prevent water uptake, have slower erosion rates and lower drug release rates. One can alter the hydrophobicity of the polymer by altering the structure and/or the content of the copolymer, thereby being able to alter the drug release rate. Since in the P(CPP-SA) and P(FAD-SA) series of copolymers, a ten-fold increase in drug release rate was achieved by alteration of the ratio of the monomers, both polymers can be used to deliver drugs over a wide range of release rates.
Several attempts were made to improve the physical properties, drug release and storage stability of polyanhydrides by using fatty acid based comonomers, using linear fatty acid chain terminals or by blending the polymers with fats and other biodegradable polymers. U.S. Pat. No. 5,171,812 to Domb et al. describes the synthesis of polyanhydrides from dimer and trimer erucic acid. These polymers were amorphous with a crystallinity in the range of 20%, hydrophobic and pliable and released the incorporated drugs for a few weeks in buffer solutions. However, these dimer fatty acid based polymers were not stable on storage at room temperature or refrigeration and rapidly decreased in molecular weight which requires storage under freezing conditions (−20° C.). Another major problem occurring with this class of polymers is their incomplete degradation and elimination from dogs after subcutaneous or intramuscular implantation probably due to the C—C bond between the two connected fatty acids.
To solve the problem of the FAD polymer elimination in vivo, diacid fat with hydrolyzable ester bond has been synthesized and evaluated as carrier for drugs. Polyanhydrides synthesized from nonlinear hydrophobic fatty acid esters based on ricinoleic, maleic acid and sebacic acid, possessed desired physico-chemical properties such as low melting point, hydrophobicity and flexibility to the polymer formed in addition to biocompatibility and biodegradability. Although these polymers were fully degradable in vivo with suitable properties as drug carriers, the major problem of storage stability and the high polydispersity remain. These polymers' molecular weight was drastically decreased within 2-3 days when stored at room temperature and the polydispersity was over 10. It was thought that a liquid polymer may release the incorporated drug too rapidity as is the case when using fatty oils.
Another attempt to obtain stable polyanhydrides that are useful for controlled drug delivery was the formation of polyanhydrides with linear fatty acid terminals (U.S. Pat. No. 5,179,189 to Domb et al.). This patent describes linear polyanhydrides made of aliphatic or aromatic diacids terminated with linear fatty acids such as stearic acid. Although these polymers possess longer drug release period and degradation time, they remain crystalline (>50%) and not pliable similar to the corresponding polymers with acid or acetyl terminals. More important, the polymers are not stable at room temperature or at refrigeration and depolymerize and hydrolyze to a low molecular weight polymer a few days of storage and form a fragile and easy to crumble polymer mass. Another attempt was the blending of polyanhydrides with biodegradable polyesters or fatty acids and triglycerides. The resulting polymeric mixtures did not form uniform blends, the polyanhydride component in the mixture degraded at a similar rate as the pure polymer leaving the hydrophobic component intact, and the storage stability did not improve.
While hundreds of polyanhydride structures are available for use as drug carriers, they suffer from a few major limitations as practical carriers for drugs. First, many of them are made of synthetic monomers, such as aromatic and heterocyclic diacid monomers, which present a risk of toxicity and slow elimination rate from an implanted animal or human (these hydrophobic co-monomers are used to control the drug release and polymer degradation). Second, these polymers are highly sensitive to heat and moisture, which makes them unstable at room temperature or even at refrigeration storage conditions which require storage at −20° C. or below. This storage stability problem is essential for a medical product to be distributed to hospitals, distribution and storage at −20° C. is very difficult logistically, expensive and impractical. The only polyanhydride device in clinical use is the GLIADEL® brain implant, which is manufactured by GUILFORD PHARMACEUTICALS®. This product requires an all time storage at −20° C. because at higher temperatures, the molecular weight of the polymer carrier drops to below 20,000 which affects the drug release rate and rejection of the device. A third problem with polyanhydrides is that polymers made of linear aliphatic acids are crystalline and fragile, which makes them impractical for use as drug carriers as they may fragment during shipment or use. The polymers used for controlled drug delivery have been solids that have to be inserted in the body during or by surgical intervention.
The presently available injectable formulations for controlled drug delivery have significant limitations. For example, ATRIGEL® (ATRIX LABORATORIES, INC.) is an injectable formulation based on a solution of poly(lactic acid) in the organic solvent, N-methylpyrrolidone (NMP). This formulation has been used for the delivery of cisplatin aminocycline, LHRH peptide and other drugs. The main limitation of this formulation is the use of NMP, an organic solvent, which must be diffused in tissue in order for the polymer to solidify into a solid delivery system. During the diffusion of the solvent out of the formulation, the drug is also washed out from the formulation which may cause a high drug release immediately after injection. REGEL® (MACROMED, Inc.) is a formulation for paclitaxel based on micellar poly(ethylene glycol) and poly(lactic acid) block copolymers (PEG-PLA) solution in water that gel in the body is now under development for treating solid tumors. This formulation is a dispersion of a polymer is water medium. Like formulation uses solvents in order to obtain a liquid formulation that can be injected and solidify into a gel in the body due to solvent extraction or temperature phase change.
There remains a strong need for an injectable liquid polymeric formulation that can be injected into solid tumors or tissue with versatility in polymer degradation and drug release profile which is stable at non freezing conditions.
It is therefore on object of the invention to provide improved injectable polymeric drug delivery formulations that are stable at non-freezing temperatures and deliver drug without causing toxicity to the patient.
It is a further object of the invention to provide improved methods for drug delivery.